Body mass index influences long-term outcome in patients with colorectal cancer.

BACKGROUND/AIMS: The influence of high Body Mass Index (BMI) on long-term outcome is scarcely known in patients with colorectal carcinoma. METHODOLOGY: In the present study was analysed 356 consecutive patients with colorectal carcinoma, in order to address the impact of BMI on patients' characteristics, surgical procedures, and clinical outcomes following radical resection. Patients were divided into the following 3 categories according to BMI; high BMI group (BMI > or = 24.0 kg/m2), middle BMI group (21.0 < or = BMI < 24.0 kg/ m2), and low BMI group (BMI < 21.0 kg/m2). RESULTS: Low BMI was significantly correlated with advanced tumor stage compared with middle BMI group (p < 0.05). The mean number of lymph node dissected per patients of the high BMI group was significantly lower than the middle BMI group (p < 0.05). The 5-year disease-free survival rates of both high and low BMI groups were significantly lower than middle BMI group, respectively. Low and high BMI also became worse independent prognostic factors by multivariate analysis, respectively (p < 0.01; low vs. middle, p < 0.05; high vs. middle). CONCLUSIONS: Both high and low BMI became independent prognostic factors of disease recurrence in patients with colorectal carcinoma, as low BMI was correlated with tumor progression and high BMI influenced the number of lymph node dissected.

Clinicopathologic features of superficial esophageal cancer: results of consecutive 100 patients.

BACKGROUND: The depth of tumor penetration is a crucial factor in determining the prognosis of patients with esophageal carcinoma. Patients with superficial esophageal carcinoma (SEC) have a far more favorable clinical course compared with those with advanced cancers. The outcome for patients with mucosal cancer is excellent with a 5-year survival rate exceeding 80%. On the other hand, submucosal cancer often metastasizes to regional and/or distant lymph nodes or other organs, and the prognosis of these patients are far from satisfactory. METHODS: Among 334 patients with esophageal cancer who underwent surgery between December 1980 and December 2006, 100 patients (30%) had SEC confined to the epithelium, lamina propria mucosa, or submucosa. Patient and tumor characteristics of those 100 patients were studied. RESULTS: The prevalence of SEC has increased from 13% (8 of 61) in the initial 5-year period (1985-1989) to 44% (41 of 93) in the recent 7-year period (2000-2006). Subjective symptoms were present in 7 (14%) of 51 mucosal cancers and in 13 (27%) of 49 submucosal cancers. The remaining 80 patients (80%) had no subjective symptoms. Ninety-one patients (91%) were diagnosed to have the lesions by endoscopy at the time of screening for gastric problems, and only nine were detected by gastrointestinal series. Four of 51 patients with mucosal cancer had venous or lymph vessel invasion, and among those, only one (2%) had a solitary perigastric lymph node metastasis. In 49 patients with submucosal cancer, 35 (71%) had lymph vessel invasion, 28 (57%) had venous invasion, and 16 (33%) had lymph node metastases. In particular, 15 of 35 patients with positive lymph vessel invasion had lymph node metastasis, whereas only 1 of 14 with negative lymph vessel invasion had lymph node metastasis (P < .05). Among 17 patients with nodal involvement, 4 patients with upper thoracic SEC had upper mediastinum and/or cervical nodal metastases, 11 patients with middle thoracic SEC had widespread upper and lower mediastinal and abdominal metastases, and 2 patients with lower thoracic SEC had lower and abdominal lymph node metastases. Seventy-nine patients were alive without recurrence at last follow-up. Five of 49 patients with submucosal cancer died of recurrent disease, and 4 of these developed regional nodal recurrence around the bilateral laryngeal recurrent nerves. Forty-two patients (42%) developed double cancers during the follow-up period, and 5 died of a second cancer. The 3- and 5-year survival rates of all 100 patients were 85% and 73%, and those disease-specific survival rates were 96% and 93%, respectively. The 3- and 5-year survival rates for patients with mucosal cancer were 89% and 83%, and those for submucosal cancer were 80%, and 64%, respectively. CONCLUSIONS: Esophagectomy with extensive lymphadenectomy should be carried out particularly for upper thoracic submucosal cancer, whereas esophagectomy with moderate lymphadenectomy may be preferred for mucosal cancer. Patients with SEC should be examined for another primary cancer preoperatively and periodically during follow-up.

Role of peroxisome proliferator-activated receptor-gamma (PPARgamma) during liver regeneration in rats.

BACKGROUND AND AIM: Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration. METHODS: Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators. RESULTS: The number of PPARgamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPARgamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group. CONCLUSIONS: These results indicate that the PPARgamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.

Lymph node classification of esophageal squamous cell carcinoma and adenocarcinoma.

The lymphatic channels of the esophagus run vertically along the axis of the esophagus and some of them drain into the cervical lymph glands upwards and into the abdominal glands downwards, and the pattern of lymph node metastasis of esophageal carcinoma is widespread. In various classifications of pattern of lymphatic spread, four classifications were proposed; location, number, ratio, and size. No definite survival advantage of aggressive lymph node dissection during esophagectomy has been proved compared with less dissection. Stage migration, micrometastasis, and sentinel lymph node concept all make it possible to individualize surgical management of esophageal carcinoma as a part of various multimodal treatments. Early diagnosis, standardization of surgery including routine lymph node dissection, and perioperative management of patients have all led to better survival rates of esophageal carcinoma.

Differential expression of RUNX genes in human esophageal squamous cell carcinoma: downregulation of RUNX3 worsens patient prognosis.

BACKGROUND: The RUNX proteins are a family of transcriptional factors that have essential functions during embryogenesis and development, whereas deregulation in expression of RUNXs is often linked to tumor formation. To date, there has been no study describing the precise expression, prognostic impact and methylation status of RUNXs in esophageal squamous cell carcinoma. METHODS: Resected specimens from 61 patients with esophageal SCC were used to identify the expression of RUNX1, RUNX2 and RUNX3 by real-time RT-PCR. Localization of mRNA was done by in situ hybridization, expression of Smad4 was evaluated by immunohistochemistry, and the methylation status of RUNX3 was analyzed by methylation-specific PCR. RESULTS: RUNX3 had a significant impact on patient prognosis with worse survival in the RUNX3-negative group. In early tumors (T1/T2), the prevalence of lymph vessel invasion and the number of metastatic lymph nodes were significantly higher in RUNX3-negative tumors. Furthermore, RUNX3 became a strong prognostic factor only in Smad4-positive tumors. Also, the methylation status of the RUNX3 promoter had a significant correlation with the loss of RUNX3 expression. CONCLUSION: Downregulation of RUNX3 may play a role in disease progression of esophageal SCC, and hypermethylation of the promoter region might be one of the crucial pathways to silence RUNX3 gene.

Expression of trefoil factor family members correlates with patient prognosis and neoangiogenesis.

PURPOSE: Trefoil factor family (TFF) peptides are thought to contribute to epithelial protection and restitution by virtue of their protease-resistant nature and their strong affinity for mucins. However, they are often overexpressed in tumors, where they seem to be negative prognostic factors, possibly contributing to tumor spread, although the precise mechanisms have not been defined. EXPERIMENTAL DESIGN: Tissue sections from 111 patients with curatively resected advanced gastric carcinoma were immunohistochemically stained for TFF2, ITF (TFF3), and CD34. Microvessel density was expressed as number and area of microvessels. Results were correlated with clinicopathological characteristics and patient survival. RESULTS: Forty-nine (44.1%) and 41 (36.9%) tumors were immunohistochemically positive for TFF3 and TFF2, respectively. Among the various clinicopathologic variables, overexpression of TFF3 had a significant correlation with patient age only. In addition, a significantly higher prevalence of positive TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis. The number of microvessels had a significant correlation with both TFF3 and TFF2 staining, whereas the area of microvessels had a significant correlation only with TFF3 staining. Both TFF3 and TFF2 were independent predictors of a worse disease-free survival. TFF3 had a gender-specific negative survival advantage, with a 91.3% disease-free survival in female patients with TFF3-negative advanced gastric carcinoma. CONCLUSIONS: Induction of increased tumor vascularity might be one of the mechanisms by which TFFs confer metastatic phenotype and frequent disease recurrence in gastric carcinomas. Female patients with TFF3-negative advanced gastric carcinoma have comparable survival as that reported for patients with early gastric carcinoma.

Metastatic lymph node size and colorectal cancer prognosis.

BACKGROUND: Colorectal cancer patients with lymph node metastasis constitute a heterogeneous population with variable prognoses. In this study, my colleagues and I propose a simpler lymph node (LN) staging system for colorectal cancer. STUDY DESIGN: Four-hundred and twenty-three consecutive colorectal cancer patients were studied. Of these, 36 were excluded because another carcinoma was present. The remaining 387 patients entered the TNM staging analysis. In the survival analysis, 76 patients with distant metastasis were excluded and the remaining 311 patients (LN(-) = 204 and LN(+) = 107) were studied. The diameter of the largest metastatic LN (MLN) was measured on histopathological slides. After examination of various cutpoints and survival outcomes, patients with MLNs were classified into n1 (< or = 9 mm) and n2 (> or = 10 mm) groups, according to size of MLNs (n-stage). RESULTS: Using disease-free survival (DFS) and overall survival (OS) as outcomes, patients were separated into significant prognostic groups by MLN size (univariate, p < 0.0001) (5-year survival, DFS: n0 = 91.5%, n1 = 62.2%, and n2 = 34.4%; OS: n0 = 85.1%, n1 = 63.5%, and n2 = 42.5%) and International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) (N-stage) (univariate, p < 0.0001) (5-year survival, DFS: N0 = 91.5%, N1 = 60.5%, and N2 = 36.8%; OS: N0 = 85.1%, N1 = 65.3%, and N2 = 38.0%). But in patients with fewer than 15 LNs examined (n = 31), only the new nodal stage stratified patients into significant groups (OS: p = 0.003 and DFS: p = 0.001). Only the UICC/AJCC N-stage subcategories were further split into significant prognostic groups by MLN size (UICC/AJCC N1: DFS, p = 0.048 and OS, p = 0.11; N2: DFS, p = 0.04 and OS, p = 0.04). n-stage was an independent important factor both in the DFS and OS in multivariable analysis. CONCLUSIONS: MLN size is a strong prognostic variable in colorectal carcinoma. This new metric may help clinicians treating colorectal cancer patients, but additional studies are required before clinical application.

Role of tumor-associated macrophages (TAM) in advanced gastric carcinoma: the impact on FasL-mediated counterattack.

BACKGROUND: Exactly what role does tumor-derived Fas ligand (FasL) play in cancer: maintaining the immune privilege site or inducing a pro-inflammatory effect? One possible hypothesis is that tumor-associated macrophages (TAM) act as the mediator that enables apoptosis of anti-tumor immune cells without FasL-related inflammation. We have evaluated the tumor FasL expression and TAM along the tumor margin and/or in cancer stroma, and their impact on the infiltration of immune-competent cells into the tumor nest. PATIENTS AND METHODS: Tissue specimens from consecutive 84 advanced gastric carcinoma patients, who had undergone a curative resection, were evaluated for TAM (CD68+ cells), tumor FasL expression and immune status (CD8 + T cells). RESULTS: A high number of TAM significantly correlated with lymph node metastasis, intestinal type tumor and FasL expression. Although TAM had a tendency for an inverse correlation with the number of CD8+ T cells within the tumor nest (nest CD8) (p=0.0592), there was no correlation between FasL expression and nest CD8 (p=0.2158). This inverse association was found to be stronger in cases with both FasL-positive and high TAM tumors than in others (p=0.0139). The combination parameter of FasL-positive and high TAM became an independent prognostic factor in Cox's multivariate analysis, along with the pT status, nest CD8 and tumor cell apoptosis. CONCLUSION: We suggest that TAM works harmoniously with tumor-derived FasL and serves as a barrier against the infiltration of CD8+ T cells into the cancer nest.

Clinical outcomes of extended esophagectomy with three-field lymph node dissection for esophageal squamous cell carcinoma.

OBJECTIVE: Opinions are conflicting about 3-field lymph node dissection (3FLND) during esophagectomy for esophageal cancer. In the current study, we sought to determine the prevalence of cervical and upper thoracic lymph node metastasis in patients with squamous cell carcinoma of the thoracic esophagus and to determine the impact of 3FLND on mortality, morbidity, survival, and recurrence rate. MATERIALS AND METHODS: Among 287 patients with squamous cell carcinoma of the thoracic esophagus seen between November 1985 and December 2001, 141 (49%) underwent extended esophagectomy with 3FLND (cervical, mediastinal, and abdominal lymph node dissection). Patients were observed and clinicopathologic information collected prospectively on all patients until death or August 2002. The median follow-up was 41 months, ranging from 10 to 173 months. RESULTS: Hospital mortality and morbidity rates were 6.4% and 80%, respectively. Thirty-four of 70 node-positive patients had cervicothoracic nodal involvement. Sixteen patients (11%) had nodal involvement confined only to the cervicothoracic nodes, and no patients with lower thoracic esophageal carcinoma showed cervicothoracic involvement alone. The frequency of cervical nodal disease was correlated with nodal status within the mediastinum (P <0.01). The 1-, 3-, and 5-year overall survival rates for all 141 patients were 76%, 58%, and 48%, respectively. Among significant variables verified by univariate analysis, independent prognostic factors for overall survival determined by multivariate analysis were number of lymph node metastasis (P <0.01), amount of blood transfusion (P <0.05), length of operation (P <0.05), and presence of pulmonary complications (P <0.05). CONCLUSIONS: Extended esophagectomy with 3FLND can be performed with an acceptable mortality. Metastases frequently involved the upper thoracic and cervical lesions, and cervical nodal disease was correlated with thoracic nodal status. 3FLND proved to be an important staging system in 11% of patients. An excellent overall survival suggests a superiority of 3FLND when performed at experienced centers.

Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.

PURPOSE: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxia-inducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas. EXPERIMENTAL DESIGN: In this study, we examined HIF [HIF-1alpha (HIF1) and HIF-2alpha (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis. RESULTS: HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T1 and T2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant. CONCLUSIONS: Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.

Extended esophagectomy with 3-field lymph node dissection for esophageal cancer.

OBJECTIVE: To review the surgical outcomes of extended esophagectomy with 3-field lymph node dissection (3FLND) for esophageal cancer. DATA SOURCES: Only articles written in English and written after 1980 were selected from MEDLINE. The following terms were identified: 3FLND, extensive or extended lymph node dissection (lymphadenectomy), radical lymph node dissection, cervical lymph node dissection, and extended or radical esophagectomy in esophageal cancer. STUDY SELECTION: There were no exclusion criteria for published information relevant to the topic. The most representative articles were selected when there were several articles from the same institution. Case reports were excluded. DATA EXTRACTION: Twenty-six articles were finally col-lected from MEDLINE. Eleven articles were also selected from reference lists of the pertinent literature. DATA SYNTHESIS: The collected information was organized. CONCLUSIONS: The conclusions drawn from those articles showed that extended esophagectomy with 3FLND would be a safe procedure in experienced hands, with low morbidity and acceptable mortality rates. When strict patient selection criteria were maintained, this procedure reduced locoregional recurrence and improved long-term survival rates. Although the therapeutic value of 3FLND is unproved in a randomized trial, extended esophagectomy with 3FLND would be the treatment of choice in selected patients.

Expression and prognostic significance of S100A2 protein in squamous cell carcinoma of the esophagus.

The purpose of this study was to evaluate the expression of S100A2 Ca2+-binding protein and its prognostic significance in the management of squamous cell carcinoma of the esophagus. Changes in cytosolic Ca2+ concentration control a wide range of cellular responses including cellular apoptosis. Intracellular S100 Ca2+-binding proteins are key molecules in transducing Ca2+ signaling. Among these, S100A2 has recently attracted major interest due to its stable expression in normal epithelia and down-regulation in some tumors. As a candidate tumor suppressor, expression of S100A2 has been proposed as a valuable prognostic marker in different tumors. We examined the clinical significance of S100A2 expression in 116 resected specimens of esophageal squamous cell carcinomas (ESCC) using immunohistochemistry. S100A2 was positive in 49 cases (42.2%) and its expression was significantly higher in large (p=0.01) and well differentiated tumors (p=0.013). Lymph node-positive tumors had a lower expression of S100A2 protein in comparison to the corresponding lymph node negative equivalents in each of the T stages, but the difference was statistically significant (p=0.041) only for the T1b tumors. S100A2 status became an independent predictor of patient survival (p=0.026) in lymph node-negative cases but not in node-positive cases. Evaluation of S100A2 protein expression may play an important role in the management of ESCC. The node-negative ESCC patients without S100A2 expression might be a high-risk group with poor survival and will need further attention to design appropriate adjuvant therapy.

Combination therapy with paclitaxel and thalidomide inhibits angiogenesis and growth of human colon cancer xenograft in mice.

BACKGROUND: Combination chemotherapy is increasingly practiced for treating malignancies with greater sensitivity and less toxicity. Paclitaxel is a potent anti-tumor agent but has dose-limiting side-effects, whereas thalidomide is an orally active anti-angiogenic drug but less than sufficient to exert anti-tumor effect as a single agent. MATERIALS AND METHODS: Nude mice bearing hypervascular (LS174T) and less vascular (HT29) colon carcinomas were challenged with either a non-cytotoxic dose of paclitaxel, thalidomide or a combination of paclitaxel and thalidomide. RESULTS: Significant growth retardation was noticed only in the combination treatment group of LS174T tumors. Microvessel density data indicated a significantly low count in the combination treatment group compared to the others. Trends of decreased expression of angiogenic growth factors and increased apoptotic index were noticed in the combination treatment group. CONCLUSION: The results of this study underscore the therapeutic efficacy of concomitant use of paclitaxel and thalidomide in the treatment of highly vascular colorectal tumors in a xenograft model.

The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients.

BACKGROUND: Tumor-associated macrophages (TAMs) have varying functions depending on the microenvironment of tumor tissue. We studied the biological role of TAMs in gastric cancer on the basis of their spatial distribution in the cancer tissue. MATERIALS AND METHODS: Tissue specimens from 84 advanced gastric carcinoma (pT2; 41 cases, pT3; 43 cases) patients who had undergone a curative resection were stained for TAM (CD68+ cells), incidence of tumor cell apoptosis (TUNEL) and host immune status (CD8+ T cells). CD68+ and CD8+ T cells infiltrated into the cancer cell nests or in close contact with cancer cells were considered as nest TAMs and nest CD8, respectively. RESULTS: Nest TAMs had a very strong direct correlation with frequency of tumor cell apoptosis (p < 0.0001) and degree of nest CD8 (p = 0.0004). The 5-year disease-free survival rate in the high-nest TAM category (87%) was significantly higher than in the low-nest TAM group (44%) (p = 0.0002). Among the several prognostic factors, nest TAM, nest CD8 and pT stage became independent predictors of patient survival (p = 0.016, p = 0.001 and p = 0.029, respectively) in Cox's multivariate analysis. CONCLUSION: These results suggested that the aggregation of TAMs within tumor nest had a beneficial effect on host in terms of augmented cytotoxicity and antigen presentation.

En-bloc esophagectomy for esophageal cancer.

BACKGROUND: The operative approach for esophageal cancer varies from simple palliative resection to extended esophagectomy with 3-field lymph-node dissection or en-bloc esophagectomy (EBE) depending on tumor and patient status and surgical strategy of the surgeon. The merits and demerits of such EBE are yet to be determined. METHODS: A literature review was done regarding EBE for esophageal cancer. RESULTS: Twenty articles describing EBE were reported from experienced institutions during the last 20 years and were selected for this study. The conclusions drawn from those articles showed that EBE would be a safe procedure with acceptable morbidity and low mortality rates when performed by an experienced surgeon. When strict patient selection criteria were maintained, this procedure decreased locoregional recurrence and improved long-term survival rates. CONCLUSIONS: EBE would be the treatment of choice in selected patients presenting with esophageal cancer. Development of meticulous preoperative risk assessment and optimum postoperative care may further improve the acceptability of this procedure with minimum morbidity and acceptable mortality rates.

Predictive factors and timing for liver recurrence after curative resection of gastric carcinoma.

BACKGROUND: Advanced and reliable diagnostic methods in order to identify the site of recurrence of gastric cancer in an early stage are needed. METHODS: One hundred twenty patients whose recurrence was confirmed after curative resection for gastric cancer were enrolled in this study. RESULTS: Liver recurrence was evident in 41 patients. Advanced age, tumor invasion into subserosa, intestinal and mixed type of histology, Borrmann type 0 to 2, tumor diameter (<6.5 cm), and tumor marker (carcinoembryonic antigen and alpha-fetoprotein) elevation were related to liver recurrence. By logistic regression analysis, independent risk factors for liver recurrence included Borrmann's classification, histology, and tumor marker elevation. The median time from the primary operation to liver recurrence was shortest in the tumor marker elevation group when compared with other independent predictors. CONCLUSIONS: This information may help to design a better follow-up program and appropriate treatment strategy for gastric cancer patients with liver metastasis.

Acute cholecystitis and cholelithiasis developed after esophagectomy.

BACKGROUND: Although the prevalence of gallstone disease after gastrectomy is reported to be high, its prevalence after esophagectomy is scarcely reported. MATERIALS AND METHODS: Gallbladder disease following an esophagectomy was prospectively evaluated in 237 patients with esophageal cancer by abdominal ultrasonography twice a year up to five years postoperatively. The median follow-up period was 18.6 months. RESULTS: One patient (0.4%) developed acute acalculous cholecystitis postoperatively, and 13 patients (5.5%) developed gallstone disease during the follow-up period. Nine (69%) of these 13 patients developed gallstone disease within two years, and another two patients developed the disease three years after esophagectomy. Another patient developed gallbladder debris at 35 months postoperatively, and one developed gallbladder polyps at 33 months. Seven of the 13 patients with gallstone disease underwent cholecystectomy between 13 and 125 months after esophagectomy: two developed acute cholecystitis; two had associated common bile duct stones; the remaining three patients had upper abdominal pain. Nine of the 13 patients who developed gallstone disease showed a history of alcoholism, whereas only 81 of 224 patients without gallstone disease had a similar history (P<0.05). CONCLUSION: A certain number of patients with esophageal carcinoma and a history of alcoholism develop cholelithiasis within three years after esophagectomy, and subsequently undergo cholecystectomy during the follow-up period.

Pattern of recurrence after extended esophagectomy for squamous cell carcinoma of the esophagus.

BACKGROUND/AIMS: To further investigate the underlying mechanism of the systemic spread of esophageal squamous cell carcinoma. METHODOLOGY: Out of 151 patients who underwent a curative esophageal resection, 41 (27.1%) developed recurrent esophageal cancer. Nine recurrences (22%) were distant-hematogenous, 17 (41.5%) non-hematogenous, and 15 (36.5%) mixed. Hematogenous deposits accompanied 58.5% of the recurrences. The relation between several clinicopathological factors and the pattern of recurrence was evaluated. RESULTS: Univariate analysis recognized the lack of adjuvant chemoradiation, the tumor location in the lower esophagus and the tumor dedifferentiation as promoting factors for hematogenous recurrence. Poorly differentiated or undifferentiated tumors presented a significantly higher microvessel density than moderately or well differentiated tumors. Tumor differentiation and tumor lower localization were independent predictors of hematogenous recurrence. CONCLUSIONS: Patients with poorly differentiated or undifferentiated tumors, which are located at the lower esophagus and present high microvessel density, should be considered at high risk for hematogenous recurrences after extended esophagectomy.

Fractalkine-CX3CR1 axis regulates tumor cell cycle and deteriorates prognosis after radical resection for hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Fractalkine is the only CX3C chemokine, and its receptor, CX3CR1, is expressed on NK cells, CD8+ T cells, monocytes, and dendritic cells (DC). Although studies have reported that fractalkine regulates the host immune response, the roles of the fractalkine-CX3CR1 axis in tumor biology and the clinical results of hepatocellular carcinoma (HCC) remain unknown. METHODS: Fractalkine and CX3CR1 expression in HCC were evaluated and compared with the clinicopathologic features, including tumor progression determined by proliferating cell nuclear antigen (PCNA) antibody and patient prognosis after surgery. RESULTS: Tumors with high expression of both fractalkine and CX3CR1 had significantly fewer intra- and extrahepatic recurrences, a low PCNA labeling index (PCNALI), and different histological grades. Patients with tumors that expressed both had a significantly better prognosis in terms of disease-free (DFS) and overall survival (OAS), and this finding was identified as one of the independent prognostic factors in the multivariate analysis. CONCLUSIONS: Our results suggest that the fractalkine-CX3CR1 axis plays a pivotal role in the prognosis of patients with HCC, which might arise from the known modulation of the host immune response, and that of the cell cycle in HCC.

FR-167653, a selective p38 MAPK inhibitor, exerts salutary effect on liver cirrhosis through downregulation of Runx2.

Liver cirrhosis remains a difficult-to-treat disease with a substantial morbidity and mortality rate. There is an emerging body of data purporting a pivotal role of the activated p38 mitogen-activated protein kinase (MAPK) in the process of cirrhosis. Several anticirrhotic agents have been developed over the past few years, and most of them exert their effects by indirectly inhibiting the p38 pathway. Effect of a selective p38 inhibitor is yet to be reported. In this study, we evaluated the salutary effect of FR-167653 (FR), a selective p38 inhibitor, in a carbon tetrachloride (CCl(4))-induced rat cirrhotic model. Twenty rats were assigned into four groups: Sham, olive oil only; Control, CCl(4) in olive oil; FR50, FR 50 mg/kg/day and CCl(4); and FR100, FR 100 mg/kg/day and CCl(4). FR dose-dependently inhibited activation of p38 and had an ameliorating effect on cirrhosis formation. Significant dose-dependent reduction in alpha-smooth muscle actin immunostaining and hydroxyproline content of the liver was noticed in the FR-treated rats. Also densitometric analysis showed a significant reduction in azan-stained area in the FR-treated rats. These fibrotic changes were observed in the myofibroblasts including the hepatic stellate cells and portal fibroblasts. mRNA expression of runt-related protein 2 (Runx2), a profibrogenic transcription factor, was significantly low in FR-treated livers, indicating that Runx2 might be a key downstream regulator of the p38 pathway. A similar reduction in expression of Smad4 and tissue inhibitor of metalloproteinase-1 was noticed in the FR-treated rats. In conclusion, FR treatment exerted a significant beneficial effect in a CCl(4)-induced rat cirrhotic model. The ameliorating effect of FR could be partially attributable to an inhibition of the Smad4/p38/Runx2 axis in the cirrhotic liver.